Asenapine or trans-5-chloro-2-methyl-2,3,3a,12b-tetrahydro-1H-dibenz[2,3:6,7]oxepino[4,5-c]pyrrole is described in U.S. Pat. No. 4,145,434 to van der Burg and it is represented by the following chemical structure:

Asenapine has CNS-depressant activity and it has antiserotonin activity. Asenapine exhibits potential antipsychotic activity and may be useful in the treatment of depression (see international patent application WO 99/32108). It has been established that the maleate salt of asenapine is a broad spectrum, high potency serotonin, noradrenaline and dopamine antagonist. A pharmaceutical preparation suitable for sublingual or buccal administration of asenapine maleate has been described in the international patent application WO 95/23600. Asenapine maleate is launched in the USA for two related indications. It is indicated for the acute treatment of schizophrenia in adults as well as for the treatment of manic or mixed episodes associated with bipolar I disorder, with or without psychotic features also in adults.
The synthetic approach for the preparation of asenapine is derivable from the teaching of U.S. Pat. No. 4,145,434 and disclosed in full Example 9 of EP 1 710 241. The last steps of this methodology are shown in the following scheme.

In Scheme 1, the double bond in the enamide, 11-chloro-2,3-dihdyro-2-methyl-1H-dibenzo[2,3;6,7]oxepino[4,5-c]pyrrol-1-one (1), is reduced to produce a mixture of a desired trans-2-isomer and an unwanted cis-2-isomer, in a 1:4 ratio. The unfavourable product ratio can be improved by subsequent partial isomerisation of the unwanted cis-2-isomer into the trans-2-isomer using DBN, leading to a thermodynamic equilibrium ratio of trans to cis of 1:2. Separation of the trans-isomer and the cis-isomer is done by chromatography over silica gel. The cis-isomer can be isomerized again using DBN and the resulting trans-isomer is again separated by chromatography. The drawback of this process is that it is extremely elaborate and time-consuming, while the final yield of the trans-isomer is only moderate.
European patent EP 1 710 241 discloses preparation of asenapine which avoids the separation of the cis-trans isomers through chromatography over silica gel. In Scheme 2, the cis-trans mixture of the compound 2 and/or its regio-isomer, 2a, preferably without separating the enantiomers, undergoes the ring-opening reaction by an excess of strong base in an alcoholic medium, yielding, predominantly, a trans-isomer of the amino-acid of the formula 3 or 3a in an approx. ratio 10:1 (trans:cis), respectively.

The trans-3 or the trans-3a may be isolated and subjected to re-cyclisation yielding the desired trans-2 or trans-2a with the overall yield of about 60% in respect of compound 1. Alternatively, compounds trans-3 or trans-3a may be converted to asenapine directly, by cyclisation with a reducing agent, optionally with a combination with a Lewis acid. In conclusion, in order to obtain the desired trans-isomer it is necessary to carry out a complex procedure involving first ring-opening to the transform and then re-cyclisation.
International patent application WO 2009/008405 provides a process for the production of asenapine in which reduction, leaving group conversion, hydrogenation and methylation are carried out in that order (see Scheme 3; X1 and X2 are the same or different and each independently represents hydrogen or halogen atom; R represents an alkyl group optionally substituted; Y represents a leaving group).

There is a need for an industrially efficient process for the preparation of asenapine with good esteroselectivity and yields.